Abstract Pancreatic cancers are devastating diseases with five year survival rate less than 7%. Currently, there is no effective treatment for advanced disease. One major barrier to efficacy of anti-tumor therapeutics is the dense desmoplastic stromal response. Evidence suggests that cancer associated pancreatic stellate cells (CAPaSC) produce the stromal collagen. The ECM laid down by CAPaSC is considered to be one of the major contributors of resistance to established therapies of the diseases. Depleting CAPaSC and altering vessel density could significantly improve efficacy of existing pancreatic ductal adenocarcinoma (PDAC) treatments. However, currently, there are no approved therapies that are able to deplete CAPaSCs in PDAC. We have developed a novel therapeutic protein (ProAgio) using rational protein design. ProAgio is designed to target integrin ?v?3 at a novel site (not the ligand binding site). ProAgio specifically induces apoptosis of integrin ?v?3 expressing cells with high efficacy by a novel mechanism of drug action (recruiting & activating caspase 8 at cytoplasmic domain of???). We reasoned that, since both CAPaSC and angiogenic endothelial cells express high levels of integrin ?v?3, and since ProAgio is very effective in inducing apoptosis of integrin ?v?3 expressing cells, ProAgio should both deplete CAPaSC and eliminate new blood vessels in and around pancreatic tumors. This unique strategy may prove advantageous in treatment of PDAC. Our STTR phase I studies demonstrated efficacy of ProAgio potentially as a PDAC treatment via various cancer models. The studies support our hypothesis that ProAgio can provide treatment benefit by simultaneously depleting the collagen-producing CAPaSCs that support tumor desmoplasia and cancer cell growth, while also eliminating newly grown cancer associated blood vessels that feed cancer cells and enable cancer metastasis. Data from our STTR phase I studies provides proof of principle for future clinical tests. To facilitate future clinical studies of ProAgio in PDAC patients, we propose to: (Aim 1) analyze the pre-clinical toxicology (TOX) and pharmacokinetics (PK) of ProAgio with rats and monkey. TOX/PK studies will enable IND application with US Food and Drug Administration (FDA). (Aim 2) Determine whether ProAgio can synergistically enhance treatment efficacy and delivery of immune checkpoint blockades. This study will explore new therapeutic avenue for PDAC patients.